Evidence map›Metformin × liver & masld›PMID 21521847›Full record

Trial reportJAMA2011

Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial.

Joel E Lavine, Jeffrey B Schwimmer, Mark L Van Natta, Jean P Molleston, Karen F Murray, Philip Rosenthal, Stephanie H Abrams, Ann O Scheimann, Arun J Sanyal, Naga Chalasani and 8 more

Registry-linked trialAbstract readMulticenter StudyRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in JAMA, 2011. The graph read 1 number from its abstract, feeding 2 cells of the map: it supports the treatment in 2. It is linked to trial NCT00063635 (Clinical Research Network in Nonalcoholic Steatohepatitis), which is not on this map. Cited by 498 papers, 15 of them syntheses that pooled it.

1number the graph read from it
2cells of the map it votes in
498citing papers in PubMed, 15 pooled it
45.9field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

← favours the treatmentfavours the comparator →
-56.90 · no effect
Liver & MASLDfavours the treatment · against placebo · liver, obesityfeeds 2 cells of the map
mean change -35.2-56.9 to -13.5
The mean change in ALT level from baseline to 96 weeks was -35.2 U/L (95% CI, -56.9 to -13.5) with placebo vs -48.3 U/L (95% CI, -66.8 to -29.8) with vitamin E (P = .07) and -41.7 U/L (95% CI, -62.9 to -20.5) with metformin (P = .40).
FeedsSupplements & botanicals×liver & masldMetformin×liver & masld

clause the extractor read what became the number

2 · Its place on the map

Where it lands on the map

Rows are treatments, columns are outcomes. The coloured squares are the cells this paper feeds, coloured by the vote it casts there. Click one to jump to what this paper adds to it.

supports the treatmentfavours the comparatorno clear differenceread, but no usable result
3 · What it changes

What it adds to each cell

For every cell the paper feeds: the belief in the claim with and without this paper, and this paper's estimate drawn against every other readable study in the cell. The ringed dot is this paper.

Metformin×liver & masld

SupportsOpen on the map →What to test next →

2 readable studies in this cell: 1 favour the treatment, 1 find no difference, 0 favour the comparator.

Belief with this paper
0.50one trial · 1 family supports, 0 contradict · against placebo
Without it
0.25This paper moves it by +0.25. It would be no deciding trial.
← favours the treatmentfavours the comparator →
0 · no effect
This paper · 2011
mean change -35.2-56.9 to -13.5
NCT02980276535 enrolled · 2017
Δ 0.00-0.30 to 0.20

Supplements & botanicals×liver & masld

SupportsOpen on the map →What to test next →

1 readable study in this cell: 1 favour the treatment, 0 find no difference, 0 favour the comparator.

Belief with this paper
0.50one trial · 1 family supports, 0 contradict · against placebo
Without itThis paper is the only evidence family behind the claim. Without it there is no number.
← favours the treatmentfavours the comparator →
0 · no effect
This paper · 2011
mean change -35.2-56.9 to -13.5
4 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT00063635 phase3completednot on this map

Clinical Research Network in Nonalcoholic Steatohepatitis: Treatment of Nonalcoholic Fatty Liver Disease in Children (TONIC)

TypeinterventionalSponsorNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)Ran2005 to 2010Enrolled173ConditionsFatty LiverArmsMetformin, Vitamin E, Matching placebo
5 · Its place in the literature

Who cites it

498 citing papers in PubMed, 15 syntheses or guidelines pooled it, 1,074 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Pooled it
  4. Guideline
  5. The Green Path to Liver Health: Herbal Solutions for Non-alcoholic Steatohepatitis.Cardiovascular & hematological disorders drug targets · 2025
    Pooled it
  6. Pooled it
  7. Vitamin E for people with non-alcoholic fatty liver disease.The Cochrane database of systematic reviews · 2024
    Pooled it
  8. Pooled it
  9. Pooled it
  10. Pooled it
  11. Pooled it
  12. Guideline
  13. Pooled it
  14. Guideline
  15. Pooled it
  16. Trial
  17. Trial
  18. Trial
  19. Trial
  20. Trial

438 more citing papers are in PubMed but not listed here.

6 · The record

Corrections and comments

7 · Who and what money

Authors and funding

18 authors at 1 institution in 1 country.

Joel E LavineDepartment of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Columbia University, New York, New York, USA. jl3553@columbia.edu
Jeffrey B Schwimmer
Mark L Van Natta
Jean P Molleston
Karen F Murray
Philip Rosenthal
Stephanie H Abrams
Ann O Scheimann
Arun J Sanyal
Naga Chalasani
James Tonascia
Aynur Ünalp
Jeanne M Clark
Elizabeth M Brunt
David E Kleiner
Jay H Hoofnagle
Patricia R Robuck
Nonalcoholic Steatohepatitis Clinical Research Network
Columbia University · US

Funding

UCSF CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTEUL1RR024131 · NCRR · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI JOHNSTON, S. CLAIBORNE · 2006 to 2011
$111.2M
ZOVIRAX CREAM TO TREAT HERPES LABIALIS IN ADOLESCENTSM01RR000827 · NCRR · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI CHANG, R JEFFREY · 1985 to 2010
$74.3M
CTSA INFRASTRUCTURE FOR PEDIATRIC RESEARCHUL1RR024989 · NCRR · CASE WESTERN RESERVE UNIVERSITY · PI DAVIS, PAMELA B · 2007 to 2011
$53.7M
INSTITUTE FOR TRANSLATIONAL HEALTH SCIENCE (UL1): BPCAUL1RR025014 · NCRR · UNIVERSITY OF WASHINGTON · PI DISIS, MARY L. · 2007 to 2011
$51.5M
Pilot Project for the DTMI CRA ProgramUL1RR024128 · NCRR · DUKE UNIVERSITY · PI CALIFF, ROBERT M · 2006 to 2010
$48.1M
ZOLENDRONIC ACID IN CHILDREN W/ SEVERE OSTEOGENESIS IMPERFECTAM01RR000188 · NCRR · BAYLOR COLLEGE OF MEDICINE · PI SHEARER, WILLIAM THOMAS · 1985 to 2011
$30.6M
ZOSUQUIDAR TRIHYDROCHLORIDE DURING CONVENTIONAL INDUCTION AND POST-REMISSIONM01RR000750 · NCRR · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI RODRIGUEZ, HENRY · 1985 to 2008
$25.5M
X-LINKED HYPOPHOSPHATEMIAM01RR000065 · NCRR · VIRGINIA COMMONWEALTH UNIVERSITY · PI SANYAL, ARUN J · 1985 to 2010
$24.8M
Pediatric Trials in Non-Alcoholic Steatohepatitis (NASH)U01DK061734 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI ROHIT LOOMBA · 2002 to 2026
$24.4M
Continuation of the Non-Alcoholic Steatohepatitis Clinical Research Network (NASHU01DK061730 · NIDDK · JOHNS HOPKINS UNIVERSITY · PI TONASCIA, JAMES A · 2002 to 2018
$23.2M
Training (Career Development) ComponentU54HD061221 · NICHD · CHILDREN'S RESEARCH INSTITUTE · PI GROPMAN, ANDREA LYNNE · 2009 to 2023
$20.8M
ZAP-70 EXPRESSION, CD38 EXPRESSION AND PROGNOSIS IN CHRONIC LYMPHOCYTIC LEUKEMIAM01RR020359 · NCRR · CHILDREN'S RESEARCH INSTITUTE · PI HINDS, PAMELA S · 2005 to 2010
$13.8M
Intramural NIH HHSNCRR NIH HHS M01 RR000065NCRR NIH HHS M01RR000065NCRR NIH HHS M01 RR000188NCRR NIH HHS M01 RR000750NCRR NIH HHS M01RR000750NCRR NIH HHS M01 RR000827NCRR NIH HHS M01RR000827NCRR NIH HHS M01RR00188NCRR NIH HHS M01 RR020359NCRR NIH HHS M01RR020359NCRR NIH HHS UL1 RR024128NCRR NIH HHS UL1RR024128NCRR NIH HHS UL1 RR024131NCRR NIH HHS UL1RR024131NCRR NIH HHS UL1 RR024989NCRR NIH HHS UL1RR024989NCRR NIH HHS UL1 RR025014NCRR NIH HHS UL1RR02501401NCRR NIH HHS UL1 RR031990NICHD NIH HHS U54 HD061221NIDDK NIH HHS K24 DK069290NIDDK NIH HHS U01 DK061713NIDDK NIH HHS U01DK061713NIDDK NIH HHS U01 DK061718NIDDK NIH HHS U01DK061718NIDDK NIH HHS U01 DK061728NIDDK NIH HHS U01DK061728NIDDK NIH HHS U01 DK061730NIDDK NIH HHS U01DK061730NIDDK NIH HHS U01 DK061731NIDDK NIH HHS U01DK061731NIDDK NIH HHS U01 DK061732NIDDK NIH HHS U01DK061732NIDDK NIH HHS U01 DK061734NIDDK NIH HHS U01DK061734NIDDK NIH HHS U01 DK061737NIDDK NIH HHS U01DK061737NIDDK NIH HHS U01 DK061738NIDDK NIH HHS U01DK061738
8 · The paper itself

Abstract

The marked sentences are the ones the graph read a number from.

contextNonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in US children and adolescents and can present with advanced fibrosis or nonalcoholic steatohepatitis (NASH). No treatment has been established.

objectiveTo determine whether children with NAFLD would improve from therapeutic intervention with vitamin E or metformin. DESIGN, SETTING, AND PATIENTS: Randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted at 10 university clinical research centers in 173 patients (aged 8-17 years) with biopsy-confirmed NAFLD conducted between September 2005 and March 2010. Interventions Daily dosing of 800 IU of vitamin E (58 patients), 1000 mg of metformin (57 patients), or placebo (58 patients) for 96 weeks.

main outcome measuresThe primary outcome was sustained reduction in alanine aminotransferase (ALT) defined as 50% or less of the baseline level or 40 U/L or less at visits every 12 weeks from 48 to 96 weeks of treatment. Improvements in histological features of NAFLD and resolution of NASH were secondary outcome measures.

resultsSustained reduction in ALT level was similar to placebo (10/58; 17%; 95% CI, 9% to 29%) in both the vitamin E (15/58; 26%; 95% CI, 15% to 39%; P = .26) and metformin treatment groups (9/57; 16%; 95% CI, 7% to 28%; P = .83). The mean change in ALT level from baseline to 96 weeks was -35.2 U/L (95% CI, -56.9 to -13.5) with placebo vs -48.3 U/L (95% CI, -66.8 to -29.8) with vitamin E (P = .07) and -41.7 U/L (95% CI, -62.9 to -20.5) with metformin (P = .40). The mean change at 96 weeks in hepatocellular ballooning scores was 0.1 with placebo (95% CI, -0.2 to 0.3) vs -0.5 with vitamin E (95% CI, -0.8 to -0.3; P = .006) and -0.3 with metformin (95% CI, -0.6 to -0.0; P = .04); and in NAFLD activity score, -0.7 with placebo (95% CI, -1.3 to -0.2) vs -1.8 with vitamin E (95% CI, -2.4 to -1.2; P = .02) and -1.1 with metformin (95% CI, -1.7 to -0.5; P = .25). Among children with NASH, the proportion who resolved at 96 weeks was 28% with placebo (95% CI, 15% to 45%; 11/39) vs 58% with vitamin E (95% CI, 42% to 73%; 25/43; P = .006) and 41% with metformin (95% CI, 26% to 58%; 16/39; P = .23). Compared with placebo, neither therapy demonstrated significant improvements in other histological features.

conclusionNeither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD.

trial registrationclinicaltrials.gov Identifier: NCT00063635.

Indexed as

AdolescentAlanine TransaminaseAntioxidantsChildDouble-Blind MethodFatty LiverFemaleHumansHypoglycemic AgentsMaleMetforminNon-alcoholic Fatty Liver DiseaseObesitySeverity of Illness IndexTreatment OutcomeVitamin EAlanine TransaminaseAntioxidantsHypoglycemic AgentsMetforminVitamin E

Identifiers

PMID21521847
PMCPMC3110082
OpenAlexW2157671355

What OpenQuestion holds

Texttitle and abstract
LicenceTDM
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.